Varicella Outbreaks Among Highly Vaccinated School Children, Arkansas and Michigan 2003 Good afternoon. Recently, CDC has been hearing about outbreaks of varicella occurring mainly in highly vaccinated populations throughout the United States. Today, I will be discussing the experiences in dealing with these outbreaks in 2 of the states in which CDC assisted with the investigations. I will also discuss some of the challenges associated with controlling outbreaks in highly vaccinated populations. Adriana S. Lopez, MHS National Immunization Program Centers for Disease Control and Prevention

Background

Varicella Vaccine Varicella vaccine licensed for use in U.S. in 1995 ACIP and AAP recommend routine varicella vaccination for children 12-18 months of age As a brief background. . . . The varicella vaccine was licensed for use in the United States in 1995 and was recommended by the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) for routine use among healthy children 12-18 months of age and for susceptible older children and adults.

Varicella Vaccine Performance Pre-licensure 70%-90% all disease >95% severe disease Post-licensure 80%-85% all disease (range, 44%-100%) >95% moderate/severe disease (range, 75%-100%) The performance of the vaccine was evaluated in pre-licensure studies where the vaccine was found to be 70%-90% effective against varicella of any severity and >95% effective against severe disease. Post-licensure studies have reported vaccine effectiveness of 80-85% (and ranging from 44%-100%) against varicella of any severity and >95% (ranging from 75%-100%) against moderate to severe disease.

Varicella Outbreak Varicella outbreaks reported in elementary schools with high varicella vaccination coverage Arkansas October 2003 in School A Michigan November 2003 in School B In October in Arkansas and November in Michigan of 2003, outbreaks of varicella were reported in school A and school B, respectively. Both schools reported high varicella vaccination coverage.

Objectives Assess the extent and severity of the outbreaks in Schools A and B Implement outbreak control measures Examine transmission patterns of varicella in these highly vaccinated populations Estimate vaccine effectiveness The objectives of the investigations in both schools were to:

Methods

Case definitions Varicella disease in unvaccinated persons: Acute generalized maculopapulovesicular rash September 1 – November 20, 2003 – School A September 1 – December 19, 2003 – School B Student or staff member Varicella in previously vaccinated persons (breakthrough disease): Varicella-like rash Vaccinated >42 days before rash onset Generally mild with ≤50 skin lesions and shorter duration of illness A case of varicella in an unvaccinated person was defined as an acute, generalized, maculopapulovesicular rash occurring between: Sept 1 and Nov 20, 2003 at school A in Arkansas OR Sept 1 and Dec 19, 2003 at school B in Michigan In a student or staff member of either school. A case of varicella in a vaccinated person (i.e., breakthrough disease) was defined as a varicella-like rash in a person vaccinated >42 days before rash onset and occurring during the period mentioned above. Breakthrough disease is generally mild, with <50 skin lesions and a shorter duration of illness.

Disease Severity Mild: < 50 lesions Moderate: 50-500 lesions Severe: > 500 lesions or complication or hospitalization Disease severity was defined based on the number of skin lesions and the occurrence of complications. Disease was classified as mild if less than 50 lesions were present; moderate if 50 to 500 lesions were present; and severe if more than 500 lesions were present, or if complications or hospitalization occurred.

Investigation Tools All students surveyed Parents of cases interviewed Demographics Disease and vaccination status Medical conditions Health care provider information and consent to contact provider Parents of cases interviewed Disease characteristics Long term medical conditions affecting immunity and their treatment Household transmission Our investigation tools consisted of two standard questionnaires. We sent surveys home with all students asking parents for information on demographics, disease and vaccination status, medical conditions, health care provider information, and consent to contact health care providers if necessary. Vaccination information was verified either by reviewing school immunization records, state registry information, or by contacting providers. Parents of cases received a follow-up telephone interview regarding disease characteristics, medical conditions that might affect immunity and treatment of the case, and information about household transmission.

Outbreak control measures Cases excluded from school until rash crusted over or lesions faded away Vaccination recommended for susceptible students and staff Exclusion of susceptible persons at high risk for severe varicella or with contraindications to vaccination Outbreak control measures included. . . . . excluding cases from school until lesions crusted or faded away, recommending vaccination for susceptible students and staff that were eligible for vaccination, AND excluding susceptible persons at high risk for severe varicella (e.g., pregnant women, immunocompromised persons) or those with contraindications to vaccination for the duration of the outbreak.

Results Results. . . . First I will present the results from the Arkansas outbreak investigation and follow with the results from the Michigan outbreak.

Arkansas Varicella vaccination coverage 88% in 2003 Day care and school entry requirements since 2000 Elementary school A K-5th grade 545 students Vaccination coverage: 96% (324/336) 27% (149/545) varicella disease history In Arkansas, the varicella vaccination coverage in 2003 was 88% for children 19-35 months of age. The national estimate for that same year was 85%. Day care and school entry requirements were implemented in 2000. School entry requirements applied to entry to K. At the time of the outbreak, students in grades K-3 were covered by the law. Elementary school A includes grades K-5 and has 545 students. Vaccination coverage in the school was 96% and 27% of students had a history of varicella disease

Arkansas Response rates: 88% (479/545) for survey 90% (44/49) cases interviewed 97% (529/545) vaccination information collected Surveys were returned by 88% of the students and 90% of the cases were interviewed. Vaccination information, which was obtained from either the survey, school immunization records, state immunization registry, or by contacting providers was collected for 97% of students.

Arkansas Varicella cases 49 cases (1 teacher, 48 students) 43 vaccinated 2 received 2 doses of vaccine 3 unvaccinated with no history 3 reported previous history 50% (3/6) specimens collected confirmed by PCR as varicella Disease mild in vaccinated cases 89% <50 lesions Missed fewer days of school (2 vs 5 days) 47% reported fever Fewer days with rash (4 vs 7 days) 49 cases of varicella were identified during the outbreak. 48 of the cases occurred in students and 1 occurred in a teacher. The teacher had a history of disease at 3 yrs of age and a history of herpes zoster at 12 yrs of age). 43 of the student cases were vaccinated (2 of those reported receiving 2 doses of varicella vaccine), 3 reported no history of disease or vaccination, and 3 reported a previous history of disease (includes the teacher). 50% (3 of 6) of the specimens collected from cases were confirmed as varicella by PCR at the CDC. Disease was generally mild in vaccinated cases. 89% had <50 lesions vs 0% in unvaccinated cases; vaccinated cases missed fewer days of school (2 vs 5 median days) compared with unvaccinated cases; fewer reported fever (47% vs 80%) compared to unvaccinated cases; and reported fewer days with rash (4 vs 7 median days). These differences were all statistically significant.

Reported varicella cases by rash onset date, grade and vaccination status*-- School A, Arkansas, 9/24-11/19/2003 (n=49**) This slide illustrates the epi curve for the outbreak at school A. The first case identified occurred in a vaccinated 2nd grader who had mild disease with about 15 lesions. The 2nd case occurred in a vaccinated 1st grader who had 50-249 lesions. As you can see from this graph, vaccinated cases played a large role in the transmission of disease in the school. Despite a vaccination coverage of 96% in the school, the outbreak lasted nearly 2 months and resulted in 49 cases. *Unvaccinated children in each grade were indicated as “grade-unvax”; all other children were vaccinated **For one child, onset date was unknown. §Onset dates (10/2) for two student cases were estimated based on the time they were first identified.

Arkansas Grade specific attack rates ranged from 0% to 26% - highest in grade 1 Attack rate in unvaccinated: 100% Attack rate in vaccinated: 18% Vaccine effectiveness Against any disease: 82% (95% CI: 76%- 87%) Against moderate/severe disease: 96% (95% CI: 92% - 98%) The grade specific attack rates ranged from 0%-26%, with 1st graders having the highest attack rates. K: 8% – 3: 0% 1: 26% – 4: 5% 2: 19% – 5: 4% The attack rate in unvaccinated persons was 100% (2/2) and in vaccinated persons it was 18% (35/192) for a vaccine effectiveness against varicella disease of any severity of 82% with 95% CI from 76%-87%. The vaccine effectiveness against moderate/severe varicella disease was 96% with 95% CI from 92%-98%. [ARu=100% (2/2); ARv=4% (6/168)] – excludes mild cases

Michigan Varicella vaccination coverage 89% in 2003 Day care requirements since 2000 and school entry requirements since 2002 Elementary school B K-3rd grade 580 students Vaccination coverage: 96% (485/507) 8% (47/554) varicella disease history Results from Michigan: In Michigan, the varicella vaccine coverage in 2003 was 89%. Day care entry requirements were implemented in 2000 and school entry requirements, for entry to K and 6th grades, were implemented in 2002. Students in K-1 and 6-7 grades were covered by the law at the time of the outbreak. Elementary school B includes grades K-3 and has 580 students. Vaccine coverage in the school is 96% and 8% of students had varicella disease history.

Michigan Response rates: 96% (554/580) for survey 95% (69/73) cases interviewed 99% (578/580) vaccination information collected 96% of students returned the survey and 95% of the cases were interviewed. Vaccination information, which was obtained from either the survey, school immunization records, or providers, was collected for 99% of students.

Michigan Varicella cases 73 cases 59 vaccinated 10 unvaccinated with no history 3 reported previous history 50% (1/2) specimens collected confirmed by PCR as varicella Disease mild in vaccinated cases 85% <50 lesions Missed fewer days of school (1.3 vs 3.5 days) 44% reported fever Reported similar days with rash (5 vs 5.5 days) 73 cases of varicella were identified during the outbreak, all among students. 59 cases were vaccinated, 10 reported no previous history of disease or vaccination, and 3 reported a previous history of disease. Disease and vaccination information was not known for 1 case. 50% (1 of 2) of the specimens collected were confirmed as varicella by PCR at CDC. Disease was mild in vaccinated cases. 85% had <50 lesions compared to 20% in unvaccinated cases; vaccinated cases missed fewer days of school (1 vs 3.5 median days) compared with unvaccinated cases; and fewer reported fever (44% vs 89%) compared to unvaccinated cases. These differences were statistically significant. Both groups reported similar # of days with rash (5 vs 5.5 median days).

Reported varicella cases by rash onset date, grade, and vaccination status-- School B, Michigan, 11/5-12/9/2003 (n=66*) The epi curve for this outbreak suggests a common source exposure for the peak of cases at the start of the outbreak. We were unable to identify any activities in or out of the school where exposure could have occurred. Again, vaccinated cases played a big role in the transmission of disease and despite high vaccination coverage, the outbreak lasted 3 generations and resulted in 73 cases. * Rash onset missing for 4 cases.

Michigan Grade specific attack rates ranged from 6% to 27% - highest in grade 3 Attack rate in unvaccinated: 77% Attack rate in vaccinated: 12% Vaccine effectiveness Against any disease: 85% (95% CI: 77%- 90%) Against moderate/severe disease: 98% (95% CI: 95% - 99%) The grade specific attack rates in school B ranged from 6%-27% with the 3rd grade having the highest attack rate. K: 6% 1: 16% 2: 7% 3: 27% The attack rate in unvaccinated persons was 77% (10/13) and in vaccinated persons was 12% (52/442) for a vaccine effectiveness against varicella of any severity of 85% with 95% CI from 77%-90%. The vaccine effectiveness against moderate to severe varicella was 98% with 95% CI from 95%-99%. [ARu=61.5%; ARv=1.8%]

Conclusion In conclusion. . . .

Outbreak Summary Large outbreaks of varicella occurred in elementary schools A and B Lasted nearly 2 months High vaccination coverage Vaccine effectiveness within the expected range Disease milder among vaccinated students Varicella in vaccinated persons contagious and can sustain transmission Large outbreaks of varicella occurred in 2 different elementary schools. The outbreaks lasted nearly 2 months, despite both schools having a vaccination coverage of 96% and vaccine effectiveness within the expected range, 82% in AR and 85% in MI. Disease among vaccinated cases was milder than in unvaccinated cases, But, varicella in vaccinated students was contagious and able to sustain transmission in both of the schools.

Discussion For discussion. . . . .

Challenges to outbreak control Diagnosis of breakthrough disease Misconceptions of breakthrough disease Surveillance/detection of outbreaks Implementation of control measures difficult Exclusion of cases Vaccination of susceptible persons Exclusion of susceptible persons Although vaccination coverage is increasing, we continue to hear about outbreaks of varicella, with more occurring among highly vaccinated populations. This is creating challenges to outbreak control. One important challenge involves the diagnosis of breakthrough disease. Diagnosis of varicella in vaccinated persons is becoming more difficult because the vaccine is modifying disease. The rash may look more like insect bites than varicella, making it more difficult for parents, school officials, and physicians to diagnose. Subsequently, children with breakthrough disease may be attending/remaining at school while infected. Therefore, as varicella incidence decreases and more cases occur among vaccinated persons, laboratory diagnosis of varicella may become necessary. Secondly, misconceptions about breakthrough disease provide challenges for control. One misconception is that breakthrough disease is not as contagious as varicella in unvaccinated persons. However, a recent study by Seward, et al looking at the infectiousness of varicella in vaccinated persons in a household setting found that vaccinated cases with >50 lesions were just as contagious as unvaccinated cases. Another misconception is that physicians/parents may think that children who have been vaccinated cannot get varicella. Thirdly, detection of outbreaks is a challenge to control because often, outbreaks are brought to the attention of public health officials once the peak of the outbreak has occurred, hindering opportunities for control. Finally, implementation of control measures is challenging because of the infectiousness of varicella and the lag in detection of outbreaks. Current control measures include: exclusion of cases, which is an effective measure for control but is challenging because diagnosis of breakthrough disease is difficult. Vaccination of susceptible persons is recommended but when most cases are already vaccinated, this method is not helpful. Finally, exclusion of susceptible persons will help limit the spread of disease but this is challenging for states to enforce, especially if no school entry requirements are in place for varicella.

Addressing challenges to outbreak control Second dose of varicella vaccine ACIP currently considering option of adding a second dose to the vaccine schedule Varicella case-based reporting Will help improve surveillance and detection of outbreaks Education on breakthrough disease So, how can we address these challenges? The addition of a second dose of varicella vaccine for children may help reduce the overall number of cases and help prevent future outbreaks. The ACIP is currently in discussions about the possibility of recommending a 2nd dose of varicella vaccine for children. A recent study looking at the efficacy of 1 vs 2 doses of varicella vaccine found a significant increase in efficacy, from 94% for the 1st dose to 98% for the 2nd dose. Additionally, the recommendation by CSTE to begin case-based reporting will help improve surveillance and early detection of outbreaks to facilitate control. Finally, education of physicians, school officials, and parents about the infectiousness and appearance of varicella in vaccinated persons is important for controlling and preventing outbreaks.

Acknowledgements CDC Arkansas Department of Health Dalya Guris Laura Zimmerman Darline El Reda Scott Schmid Vladimir Loparev Aisha Jumaan Arkansas Department of Health Sandra Snow Linda Gladden Dirk Haselow Tiffany Wilder Ava Kelley Michigan Department of Community Health Joel Blostein Richard Renas Shane Bies Carol Bird Matthew Boulton School nurses and staff in Arkansas and Michigan Lastly, I would like to acknowledge all of those who put in many hours helping with the investigations and analysis.

Thank You